<!-- Definition and medical uses -->

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is given by slow intravenous infusion.

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The most common side effects with intravenous infusions are reactions related to the infusion (such as fever, chills and shivering) while most common serious side effects are infusion reactions, infections and heart-related problems. It is unclear if use during pregnancy is safe for the developing fetus or newborn baby. It is on the World Health Organization's List of Essential Medicines. Rituxan is co-marketed by Biogen and Genentech in the US, by Roche elsewhere except Japan, and co-marketed by Chugai Pharmaceuticals and Zenyaku Kogyo in Japan.

Medical uses

Rituximab is a chimeric monoclonal antibody targeted against CD20, a surface antigen present on B cells. It acts by depleting normal as well as pathogenic B cells while sparing plasma cells and hematopoietic stem cells, which do not express the CD20 surface antigen.

In the United States, rituximab is indicated to treat:

  1. non-Hodgkin lymphoma

In the European Union, rituximab is indicated for the treatment of follicular lymphoma and diffuse large B cell non-Hodgkin's lymphoma (two types of non-Hodgkin's lymphoma, a blood cancer); This also includes Waldenström's macroglobulinemia, a type of non-Hodgkin lymphoma. It is used in combination with fludarabine and cyclophosphamide to treat previously untreated and previously treated CD20-positive chronic lymphocytic leukemia.

Autoimmune diseases

Rituximab has been shown to be an effective rheumatoid arthritis treatment in three randomised controlled trials and is now licensed for use in refractory rheumatoid disease. In the United States, it has been FDA approved for use in combination with methotrexate for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more anti-TNF-alpha therapy. In the European Union, the license is slightly more restrictive: it is licensed for use in combination with methotrexate in patients with severe active RA who have had an inadequate response to one or more anti-TNF therapy.

There is some evidence for efficacy, but not necessarily safety, in a range of other autoimmune diseases, and rituximab is widely used off-label to treat difficult cases of multiple sclerosis, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy and autoimmune anemias. The most dangerous, although among the most rare, side effect is progressive multifocal leukoencephalopathy infection, which is usually fatal; however, only a very small number of cases have been recorded occurring in autoimmune diseases.

Other autoimmune diseases that have been treated with rituximab include autoimmune hemolytic anemia, pure red cell aplasia, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis (e.g., granulomatosis with polyangiitis), bullous skin disorders (for example, pemphigus, pemphigoid—with very encouraging results of approximately 85% rapid recovery in pemphigus, according to a 2006 study), type 1 diabetes mellitus, Sjögren's disease, anti-NMDA receptor encephalitis and Devic's disease(Anti-AQP4 disease, MOG antibody disease), Graves' ophthalmopathy, autoimmune pancreatitis, Opsoclonus myoclonus syndrome (OMS), and IgG4-related disease. There is some evidence that it is ineffective in treating IgA-mediated autoimmune diseases.

Adverse events

Serious adverse events, which can cause death and disability, include:

  • Progressive multifocal leukoencephalopathy caused by JC virus reactivation
  • Hepatitis B reactivation
  • Other viral infections
  • Immune toxicity, with depletion of B cells in 70% to 80% of lymphoma patients
  • Pulmonary toxicity
  • Bowel obstruction and perforation

A concern with continuous rituximab treatment is the difficulty to induce a proper vaccine response. This was brought into focus during the COVID-19 pandemic, where persons with multiple sclerosis and rituximab treatment had higher risk of severe COVID-19. In persons previously treated with rituximab for multiple sclerosis, nine of ten patients who delayed re-dosing until B cell counts passed 40/μL developed protective levels of antibodies after vaccination with the Pfizer–BioNTech COVID-19 vaccine.

Mechanisms of action

thumbnail|right|Rituximab mechanisms of action; the three major independent mechanisms are (1) antibody dependent cellular cytotoxicity (ADCC), (2) complement mediated cytotoxicity (CMC), and (3) apoptosis; subset panel illustrates a schematic view of CD20 structure and rituximab.

thumbnail|right|Rituximab binding to CD20. The CD20 proteins are sticking out of the cell membrane, and rituximab, the Y-shaped antibody, is binding to the CD20 proteins.

The antibody binds to the cell surface protein CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. Although the function of CD20 is unknown, it may play a role in Ca<sup>2+</sup> influx across plasma membranes, maintaining intracellular Ca<sup>2+</sup> concentration and allowing activation of B cells.

Rituximab is relatively ineffective in elimination of cells with low CD20 cell-surface levels. It tends to stick to one side of B cells, where CD20 is, forming a cap and drawing proteins over to that side. The presence of the cap changes the effectiveness of natural killer (NK) cells in destroying these B cells. When an NK cell latched onto the cap, it had an 80% success rate at killing the cell. In contrast, when the B cell lacked this asymmetric protein cluster, it was killed only 40% of the time.

The following effects have been found:

  • The Fc portion of rituximab mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
  • Rituximab has a general regulatory effect on the cell cycle.
  • Preferential elimination of malignant B cells with high CD20 levels and high BCR signaling propensity, especially in chronic lymphocytic leukemia (CLL).

History

Rituximab was developed by IDEC Pharmaceuticals under the name IDEC-C2B8. The US patent for the drug was issued in 1998 and expired in 2015.

Based on its safety and effectiveness in clinical trials, rituximab was approved by the US Food and Drug Administration (FDA) in 1997 to treat B-cell non-Hodgkin lymphomas resistant to other chemotherapy regimens. Rituximab, in combination with CHOP chemotherapy, is superior to CHOP alone in the treatment of diffuse large B-cell lymphoma and many other B-cell lymphomas. In 2010, it was authorized by the European Commission for maintenance treatment after initial treatment of follicular lymphoma.

It is on the World Health Organization's List of Essential Medicines.

In June 2017, the US FDA granted regular approval to the combination of rituximab and hyaluronidase human (brand name Rituxan Hycela) for adults with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. The combination is not indicated for the treatment of non-malignant conditions. Rituximab was approved by the FDA to treat adults with granulomatosis with polyangiitis and microscopic polyangiitis in 2011. Efficacy was evaluated in Inter-B-NHL Ritux 2010, a global multicenter, open-label, randomized 1:1 trial of participants six months in age or older with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or B-cell acute leukemia. Ituxredi was authorized for medical use in the European Union in September 2024.

A Rituximab biosimilar was approved in India in 2007.

Economics

In 2014, Genentech reclassified Rituxan as a specialty drug, a class of drugs that are only available through specialty distributors in the US. Because wholesalers discounts and rebates no longer apply, hospitals would pay more. and in the United States. Biosimilars were approved in the United States, India, the European Union, Switzerland, Japan, and Australia. The US FDA approved rituximab-abbs (Truxima) in 2018, rituximab-pvvr (Ruxience) in 2019, Truxima and Riabni are approximately $3600 per 500&nbsp;mg, wholesale - 10% less than Rituxan, while Ruxience is 24% less than Rituxan. The Indian biosimilar ituxredi retails for about 1/6 the price.

Tailored-dosing

Tailored-dose rituximab is more cost-effective than fixed-dose. It is both more effective and less expensive.

Research

Rituximab has been reported as a possible cofactor in a chronic hepatitis E infection in a person with lymphoma. Hepatitis E infection is normally an acute infection, suggesting the drug in combination with lymphoma may have weakened the body's immune response to the virus.

Myalgic encephalomyelitis/chronic fatigue syndrome

In 2009, a patient receiving methotrexate-induced B-cell depletion for cancer treatment, experienced a transient remittal of their myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms. While initial trials using Rituximab were promising, a phase 3 trial published in 2019 did not find an association between Rituximab treatment and improvements in ME/CFS.

Intrathecal

For CNS diseases, rituximab could be administered intrathecally and this possibility is under study.

Other anti-CD20 monoclonals

The efficacy and success of rituximab has led to some other anti-CD20 monoclonal antibodies being developed:

  • ocrelizumab, humanized (90%-95% human) B cell-depleting agent.
  • ofatumumab (HuMax-CD20) a fully human B cell-depleting agent.
  • Third-generation anti-CD20s such as obinutuzumab have a glycoengineered Fc fragment (Fc) with enhanced binding to Fc gamma receptors, which increase ADCC (antibody-dependent cellular cytotoxicity). This strategy for enhancing a monoclonal antibody's ability to induce ADCC takes advantage of the fact that the displayed Fc glycan controls the antibody's affinity for Fc receptors.

References

Further reading